This invention relates to devices useful for the delivery of a beneficial agent to an environment of use.
There are many devices in which exogenous agents (triggers) such as enzymes, enzyme substitutes, antibodies, heat, light, nucleophiles and changes in pH interact with a device release barrier such as a coating or matrix in such a way as to remove the barrier and consequently release the active ingredient. For example, there are polymeric membrane delivery systems which, in response to external stimuli, undergo a change in permeability, or a change in erosion rates (Pitt, C. G., Z.-W. Hendren, Z-W., J. Thompson, and M. C. Wani, "Triggered Drug Delivery Systems," in Advances in Drug Delivery Systems, Anderson and Kim (eds.), Elsevier, Amsterdam (1985) p. 363; Heller, J. and S. H. Pangburn, S. H., "A Triggered Bioerodible Naltrexone Delivery System," in Proceedings of the 13th International Symposium on Controlled Release, 1986 p. 35). In both cases the physical or chemical nature of the polymeric membrane itself is altered in response to the trigger.
In addition, osmotic-bursting systems have been developed that are initiated in the presence of water and thus are "triggered" upon ingestion or in a humid environment (Ueda, S., R. Ibuki, Hata, and Y. Ueda, "Design and Development of Time-controlled Explosion System (TES) as a Controlled Drug Release Systems," Proceed. Intern. Syrup. Control. Rel. Bioact. Mater., 15 (1988) 450; Baker, U.S. Pat. No. 3,952,741; and Theeuwes and Damani, U.S. Pat. No. 4,016,880).
Another common trigger for drug release is solution pH (e.g. enteric coatings). For example, enteric coatings consisting of cellulose acetate phthalate, resist action of duodenum fluids, but readily disintegrate in the ileum. (Remington's Pharmaceutical Sciences, J. E. Hoover, ed. Mack Publishing Co., Easton, Pa. (1970) pp 1689-1690).
Temperature triggered systems include hydrogels of N-isopropylacrylamide (NIPA) and other n-alkyl acrylamides that swell and contract in response to different temperatures (Hoffman, A. S., "Application of Thermally Reversible Polymers and Hydrogels in Therapeutics and Diagnostics," in Advances in Drug Delivery Systems, 3, Anderson and Kim (eds.), Elsevier, Amsterdam (1987) p. 297; Bae, Y. H., K. Mukae, K., T. Okano, and S. W. Kim, "On-Off Transport Regulation through Thermosensitive Hydrogels," Proceed. Intern. Symp. Control. Rel. Bioact. Mater., 17 (1990) 19). In addition, polymers with temperature-sensitive side chains have been developed for temperature-triggered delivery of agrichemicals and drugs (Stewart, R. F., "Temperature Controlled Active Agent Dispenser," U.S. Pat. No. 4,830,855 (1989)).
Polymers that change permeability due to exposure to light have been described (Smets, G. "New Developments in Photochromic Polymers," J. Polym. Sci., Polym. Chem. Ed., 13 (1975) 2223). in addition, delivery systems have been developed that are based on photochemical reactions. Delivery of active agents by photo-induced cleavage of covalent bonds that attaches an active ingredient to a polymer backbone have also been described, although this method of delivery does not rely on a change of coating permeability. In another photochemical-based system, polyamide microspheres were formed from aqueous solutions of diamine (ethylene diamine or hexamethylene diamine) or triamine (diethylenetriamine) and polyvinyl alcohol, which were added to terephthaloyl chloride in benzene/xylenes. Irradiation with UV light caused generation of N.sub.2, bursting the microspheres (Mathiowitz, E., M. D. Cohen, and R. Langer, R., "Novel Microcapsules for Delivery Systems," Reactive Polymers, 6 (1987) p. 275).
Systems that rely on magnetic or ultrasound triggers have also been devised (Peppas, N. A. and L. S. Flosenzier, Life Support Syst., 4 (Suppl. 2) (1986) 395.; Langer and Kost, in Pulsed and Self-Regulated Drug Delivery, Kost (ed.), CRC Press, Boca Raton, Fla. (1990) pp. 3-9; Langer, R. S. and J. Kost, U.S. Pat. No. 4,657,543). These triggers increase the rate of diffusion through polymeric matrices.
Systems have also been described for which release of a pharmaceutical is triggered by metabolite concentration, such as insulin release triggered by glucose concentration (Pitt, C. G., Z.-W. Hendren, J. Thompson, and M. C. Wani, "Triggered Drug Delivery Systems," in Advances in Drug Delivery Systems, Anderson and Kim (eds.), Elsevier, Amsterdam (1985) p. 363).
Methods for enzyme-triggered release of pharmaceuticals are also known. These enzyme-triggered systems are based on enzymatic action on a solid substrate. In one system, the active agent is dispersed in pH-sensitive polymer, which erodes at pH 7.4. This is surrounded by enzyme-degradable hydrogel, which is surrounded by a reversibly inactivated enzyme capable of degrading the enzyme-degradable hydrogel. The enzyme is reversibly inactivated by covalent attachment of the hapten (triggering agent) and complexation with antibody against hapten (Heller, J., "Use of Enzymes and Bioerodible Polymers in Self-regulated and Triggered Drug Delivery Systems," in Pulsed and Self-regulated Drug Delivery Systems, J. Kost (ed.), CRC Press, Boca Raton, Fla. (1990) p. 93).
In other systems, enzymes (or the physiological environment) degrade the polymeric membrane itself, leading to release of the active ingredient. In general, enzymatic reaction with solids is very slow, making rapid release impossible (D. L. Wise (Ed.), Biopolymeric Controlled Release Systems, CRC Press, Boca Raton, Fla. (1984)).
Another triggered system consists of a cyclic moiety with an enzyme-sensitive side chain. Cleavage of the side chain leaves a group capable of attacking another carbonyl based side chain to form a cyclic lactone (lactam) and releasing the structure originally bound to the carbonyl side chain (Arnost, Michael J., F. Meneghini, and P. S. Palumbo, Polaroid Corp., "Enzyme Controlled Release System and Organic Conjugate Systems" WPO 88/05827 (i.e. U.S. Pat. No. 5,034,317)). This is a particular type of enzyme-sensitive pro-drug, and no protective membrane is involved.
In another enzymatic triggered system, apple pectin, which is only degraded by colonic flora, is used as a carrier for drugs. Release of indomethacin was enhanced in solutions containing pectolytic bacteria B. ovatus and Klebsiella oxytoca but not in controls or in solutions containing human E. coli, which does not have high pectolytic activity (Rubenstein, A., S. Pathak, M. Friedman, and J. S. Rokem, Proceed. Intern. Syrup. Control. Rel. Bioact. Mater., 17 (1990) 466). This system also does not involve a protective membrane, but rather a carrier matrix.
In yet another system albumin-crosslinked polyvinylpyrrolidone gels were used as enzyme-degradable hydrogels. Enzymatic degradation of the albumin crosslinks increased the water swelling of the hydrogel (Shalaby, W. S. W., W. E. Blevins and K. Park, "Enzyme-Digestible Properties Associated with Albumin-Crosslinked Hydrogels for Long-Term Oral Drug Delivery," Proceed. Intern. Symp. Control. Rel. Bioact. Mater., 17 (1990) 134).
In another enzymatic triggered system urease-catalyzed conversion of urea raises the pH, which enhances dissolution of methyl vinyl ether-maleic anhydride partial ester copolymer (Heller, J., R. W. Baker, R. M. Gale, R. M., and J. O. Rodin, "Controlled Drug Release by Polymer Dissolution I. Partial Ester of Maleic Anhydride Copolymers," J. Appl. Polym. Sci., 22 (1978) 1991).
In yet another system hydrogels based on acrylic acid, N,N,-dimethylacrylamide and N-tert-butyl-acrylamide, crosslinked with 4,4'-di(methacryloylamino)azobenzene, were synthesized for site-specific delivery of pharmaceuticals to the colon. These hydrogels exhibit low equilibrium swelling at gastric pH. Swelling increases as the gel passes down the GI tract, exposing azo linkages to colonic azoreductases, which cleave the crosslinks, releasing drug dispersed in the gel (Brondsted, H., and J. Kopecek, Proceed. Intern. Symp. Control. Bel. Bioact. Mater., 17(1990)128).
Although the above triggered release devices make a considerable advance in the art there is a continuous search in this art for alternative triggered release devices that allow release over a wide variety of time frames and enable the delivery of a wide variety of active ingredients.
In another field of art, the field of chemical separation, supported-liquid membranes (SLM's) have been used as separation membranes as an alternative to solvent extraction. SLM's comprise a liquid held in the pores of a synthetic membrane (Way, J. D., R. D. Noble, T. M. Flynn, and E. D. Sloan, "Liquid Membrane Transport: A survey," J. Membrane Sci., (1980) 239-259). SLM's prevent mixing of the solutions that they separate. As such they serve to compartmentalize and protect the two solutions involved in the separation. The ability of an SLM to maintain separation between two solutions can vary. This separation maintenance has been extensively studied (H. Takeuchi, K. Takahashi, and W. Goto, "Some Observations on the Stability of Supported Liquid Membranes," J. Membrane, Sci., 34(1987) 19-31; P. R. Danesi, L. Reichley-Yinger, and P. G. Richert, "Lifetime of Supported Liquid Membranes: The Influence of Interfacial Properties, Chemical Composition and Water Transport on the Long-Term Stability of the Membranes," J. Membrane Sci., 31 (1987) 117-145; Takeuchi, H., and M. Nakano, "Progressive Wetting of Supported Liquid Membranes by Aqueous Solutions," J. Membrane Sci., 42 (1989) 183-188; Kim, B.-S. and P. Harriot, "Critical Entry Pressures for Liquids in Hydrophobic Membranes," J. Colloid, Interface Sci., 1115 (1987) 1).
The use of SLM's for a transdermal delivery system has been described (Merkle, H. P., A. Knoch, and G. Gienger, "Release Kinetics of Polymeric Laminates for Transdermal Delivery: Experimental Evaluation and Physical Modeling," In Advances in Drug Delivery Systems, Anderson and Kim (eds.), Elsevier, Amsterdam (1986) p. 99). The device consists of polymeric laminates in which one layer consists of a microporous membrane. The pores of the membrane are filled with a non-polar (i.e. mineral oil, paraffin) media. In these systems release occurs by permeation of the drug through the membrane pore-filling media, providing release of the active ingredient.
PCT Publication WO 92/05775 "Dispensing Device Containing a Hydrophobic Medium" describes a delivery system for the dispensing of an insoluble agent to an aqueous environment. The device comprises a beneficial agent in a hydrophobic medium surrounded by a wall which is in part permeable to the beneficial agent-containing hydrophobic medium. The permeable portion of the wall may be porous with a hydrophobic medium entrained in the pores of the wall.
Although these SLM release devices make a significant advance in the art there is a continuing search for alternative SLM release devices.